The functional avidity of a CD8+ T cell correlates with the magnitude of its effector function. High avidity are more effective than low avidity CD8+ T cells in clearing virus in vivo. Antigen density is one factor that controls avidity, however it is likely that other factors are involved in the determination of avidity. The goal of these studies is to determine the role of CD4+ T helper cells in the generation of a high avidity CD8+ T cells following intranasal immunization of mice with the paramyxovirus simian virus 5. In this model, the number of high avidity CD8+ T cells is severely reduced in CD4-depleted mice, suggesting that CD4+ T cell "help" provided by CD40/CD40L-mediated APC activation and/or cytokine secretion influence CD8+ T cell avidity. The role of APC activation in the generation of CD8+ T cell avidity will be determined in mice deficient for CD40. The role of T helper cytokines in the generation of high avidity CD8+ T cells will be determined by identifying candidate cytokines and analyzing cytokine receptor expression on CD8+ T cells. The necessity and sufficiency of the candidate cytokine for high avidity CD8+ T cell responses will also be assessed. These studies will determine whether APC-derived signals and/or cytokines promote the activation, survival or expansion of high avidity CD8+ T cells. Knowledge of the factors that control the functional avidity may lead to more efficacious vaccines that elicit high avidity CD8+ T cell responses.